Diabetic nephropathy is the leading cause of end stage renal disease in the United States. Diffuse mesangial expansion is a major component of diabetic nephropathy. By crowding out open capillary loops, this mesangial expansion eventually results in end-stage renal failure. This proposal will attempt to show how diabetes results in mesangial expansion. The PI has recently discovered that diabetes is associated with the loss of a novel specific inhibitor (INHIB), mw> 8,000. He believes-that INHIB is ordinarily embedded in the mesangial extracellular matrix of the kidney. INHIB prevents excessive mesangial matrix expansion. In diabetes, INHIB is absent or non-functional. This results in excessive mesangial expansion and-ultimately renal failure. The specific aims of the proposed experiments follow. I) To purify INHIB. II) To prepare monoclonal antibodies against INHIB. III) To determine why INHIB is nonfunctional in the diabetic renal mesangium. IV) To determine the effect of INHIB on mesangial cell matrix production and proliferation. V) To use the monoclonal antibodies to determine the organ distribution of INHIB in normal and diabetic mice, and to compare the molecular characteristics of INHIB in these mice. By understanding the biochemistry and biology of INHIB, and its absence in diabetic nephropathy, new therapeutic approaches to this major cause of renal failure may eventually be developed.